Book/Report

FZJ-2019-01719

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Untersuchungen zur Synthese und Stabilität radiopharmazeutisch relevanter Metall-Chelat-Peptid-Systeme

Brockmann, J. (Corresponding author)FZJ*

1996
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag Jülich

Please use a persistent id in citations: http://hdl.handle.net/2128/21768

Report No.: Juel-3316

Abstract: Labelling of bioactive molecules with radioactive metal-ions is one major field of chemistry engaged in nuclear medicine. In most cases radiolabelling with radiometals requires multidentate ligands to obtain high in vive stabilities of the radiopharmaceuticals. In this work two important aspects of metal-ligand-linker-peptide-systems were explored. First the $^{88}$Y-DTPA-peptide-system was investigated with regard to complexation kinetics, stability constants and lipophilicity to obtain information about the radiodiagnostical $^{86}$Y- [DTPA-(D)Phe$^{1}$]-Octreotide and the potential endotherapeutical $^{90}$Y-[DTPA-(D)Phe$^{1}$]-Octreotide. The second aspect includes the insertion of different linker structures in [DFO-B-Succinyl-(D)Phe$^{1}$]-Octreotide type radiopharmaceuticals to modify its pharmakokinetic properties. Initially four DTPA-peptides containing phenylalanine as N-terminal amino acid were synthesised via the bisanhydride method. The decomplexation kinetics of these $^{88}$Y-DTPA-peptides were determined by using the isotopic exchange method. The decomplexation kinetics of the Y-DTPA-peptide-system were shown to be independent of competing metaIions. It is mostly affected by the pH of the solution in a multistep manner but should be nearly inert against decomplexation under physiological conditions (pH 7.4). To calculate thermodynamic stability constants of multidentate ligands attached to peptides or proteins a novel route was developed. This calculation mode is based on ligand-ligand-exchange reactions with small amounts of the metal-ion taking the advantage to measure activity ratios using carrier-free $^{88}$Y. Furthermore the protonation constants of the basic sites of the chelator were determined along these reactions. The calculate stability constant of Y-DTPA-üeütides (log $\beta$ approx. 19.0 $\pm$ 0.5) and $^{88}$Y-[DTPA-(D)Phe$^{1}$]-Octreotide (log $\beta$ = 19.25 $\pm$ 0.05) are in good accordance to values determined by standard methods. In animal studies with tumour bearing rats the applicability of $^{86}$Y-[DTPA-(D)Phe$^{1}$]-Octreotide as a PET-tracer for somatostatin receptor scintigraphy was tested. Although the Octreotide derivative has high receptor affinity the release of the metal-ion in vive lead to high bone uptake and the low lipophilicity of the tracer to a high kidney accumulation. For the second Octreotide derivative $^{67}$Ga-[DFO-B-Succinyl-(D)Phe$^{1}$]-Octreotide a higher in vivo stability was expected. To affect the pharmakokinetic properties of $^{67}$Ga-DFO labelled Octreotides a synthesis route was developed for insertion of variable Iinkers instead of succinic acid. Different disuccinimidylic esters of dicarboxylic acids were tested for conjugation of $^{67}$Ga-DFO to peptides. Applying these reaction conditions, $^{67}$Ga-[DFO-B-glutaryl-(D)Phe$^{1}$]-Octreotide and $^{67}$Ga-[DFO-B-suberyl-(D)Phe$^{1}$]-Octreotide were synthesised. Increasing Iipophilicity of these compounds reduced their kidney accumulation. Interestingly for the glutaryl derivative a higher hydrophilicity (logP = -1.85) was measured compared to the succinyl form (logP = -1.56). In a rat model the three different $^{67}$Ga-DFO-Octreotides showed high uptake in organs with expected large amounts of somatostatin receptors but different kidney-to-liver excretion ratios depending on their lipophilicity.

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Contributing Institute(s):

1. Publikationen vor 2000 (PRE-2000)

Research Program(s):

1. 899 - ohne Topic (POF3-899) (POF3-899)

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